08/13/2014 – 21:42
Making viruses in the lab deadlier and more able to spread: an accident waiting to happen
Tatyana Novossiolova , Malcolm Dando
All rights come with limits and responsibilities. For example, US Supreme Court Justice Oliver Wendell Holmes famously noted that the right to free speech does not mean that one can falsely shout “fire” in a crowded theatre.
The same constraints and obligations apply to the right of scientific inquiry, a topic that has been in the news recently after researcher Yoshihiro Kawaoka of the University of Wisconsin-Madison published an article in the journal Cell Host and Microbe in June revealing that he had taken genes from the deadly human 1918 Spanish Flu and inserted them into the H5N1 avian flu to make a new virus—one which was both far deadlier and far more capable of spreading than the original avian strain. (The 1918 Spanish Flu killed an estimated 50 million people; the molecular structure of the new combined avian/human strain is only three percent different than the 1918 version.)
Asked for comment by The Guardian newspaper, Robert, Lord May of Oxford, the former chief scientific advisor to the British Prime Minister and former president of the British Royal Society—one of the oldest and most prestigious scientific organizations in the world—condemned the work as “absolutely crazy,” calling “labs of grossly ambitious people” a real source of danger.
As if that research were not enough to cause worry, in July a newspaper investigation asserted that Kawaoka was also conducting another controversial—but so far unpublished—study in which he genetically altered the 2009 strain of flu to enable it to evade immune responses, “effectively making the human population defenseless against re-emergence.”
If true, it may be that Kawaoka has engineered a novel strain of influenza with the capability of generating a human pandemic, if it ever escaped from a laboratory. (“Pandemic” means that it occurs over a wide geographic area and affects an exceptionally high proportion of the population. In comparison, the Centers for Disease Control define an “epidemic” as merely “the occurrence of more cases of disease than expected in a given area or among a specific group of people over a particular period of time.”)
An independent risk-benefit assessment of this work conducted at the request of the journal Nature demonstrated that Kawaoka’s work did indeed meet four of the seven criteria outlined in the US Policy for Oversight on Dual Use Research of Concern (DURC) of March 29, 2012, meaning that the institution found that the research could be misused to threaten public health and would therefore require additional high-level safety measures, including a formal risk-mitigation plan.
But even with these measures in place, this research still seems like an unnecessary risk, given the danger that the bio-engineered viruses could turn into a pandemic threat, and that some experts think that there are far better and safer ways to unlock the mysteries of flu transmissibility. Claims that this work would help in the manufacture of a preventive vaccine have been strongly contradicted by Stanley Plotkin of the Center for HIV-AIDS Vaccine Immunology, among other critics.
Part of the justification behind conducting these experiments, apparently, was to develop a better understanding of the pandemic potential of influenza viruses by enhancing their properties, such as altering their host range, for example. Since the newly engineered viruses possess characteristics that their naturally found, or “wild,” counterparts do not, this type of study is commonly referred to as “gain-of-function” research in virologists’ parlance.
But considering the likelihood of accidental or deliberate release of the virus created by gain-of-function experiments, the following issues should be considered before approving any such studies—and preferably they would have been taken into consideration by those attending the Biological and Toxin Weapons Convention earlier this month.
In a nutshell: The Convention’s attendees should have agreed on a common understanding requiring that all gain-of-function experiments be stopped until an independent risk-benefit assessment is carried out; the scientific community should exhaust all alternative ways of obtaining the necessary information before approving gain-of-function experiments; biosecurity education and awareness-raising should be given a priority as tools for fostering a culture of responsibility in the life sciences; and there should be a modern version of the “Asilomar process” to identify the best approaches to achieving the global public health goals of defeating pandemic disease and assuring the highest level of safety. (At Asilomar, California, in the early 1970s, researchers studying recombinant DNA met to discuss whether there were risks from their research, what the negative social implications could be, and how to contain the dangers.)
There will be another meeting of the Biological and Toxin Weapons Convention in December; one can only hope that it will consider these proposals then.
What, me worry? Sometimes, the potential for accidents is inherent in a system, making their occurrence not only able to be anticipated but inevitable, even “normal.” For example,Charles Perrow’s famous account of the Three Mile Island nuclear accident contends that the very structure and organization of nuclear power plants make them accident-prone. As a result, even in the presence of sophisticated safety designs and technical fixes, multiple and unexpected interactions of failures are still bound to occur, as illustrated more recently in the Fukushima disaster.
Gain-of-function research in the life sciences is another example of the inevitable failure of overly complex, human-designed systems with multiple variables. Some of the most dangerous biological agents—anthrax, smallpox, and bird flu—have been mishandled in laboratories. As noted by the newly formed Cambridge Working Group, of which one of us —Malcolm Dando—is a member, these are far from exceptional cases; in the U.S. alone, biosafety incidents involving regulated pathogens “have been occurring on average over twice a week.”
Such situations are not confined to the United States; China’s poor track record for laboratory containment means that it was “appallingly irresponsible” (in Lord May’s words) for a team of Chinese scientists to create a hybrid viral strain between the H5N1 avian influenza virus and the H1N1 human flu virus that triggered a pandemic in 2009 and claimed several thousand lives. In a July 14, 2014 statement about the creation of such pathogens, the Cambridge Working Group noted:
An accidental infection with any pathogen is concerning. But accident risks with newly created “potential pandemic pathogens” raise grave new concerns. Laboratory creation of highly transmissible, novel strains of dangerous viruses, especially but not limited to influenza, poses substantially increased risks. An accidental infection in such a setting could trigger outbreaks that would be difficult or impossible to control.
Against this backdrop, the growing use of gain-of-function approaches for research requires more careful examination. And the potential consequences keep getting more catastrophic.
High-profile examples. In April, 2014, the Daniel Perez Lab at the University of Maryland engineered an ostrich virus known as H7N1 to become “droplet transmissible”—meaning that the tiny amounts of virus contained in the minuscule airborne water droplets of a sneeze or a cough would be enough to make someone catch the illness. Hence, it could be easily transmitted from one subject to another.
So far, there has not been one laboratory-confirmed case of human infection by H7N1. It is apparently not a threat to man, unlike H5N1 and H7N9.
However, while the chance of airborne transmission of H7N1 in humans by droplet is apparently low, the test animals that it did manage to infect became very ill indeed—60 percent of ferrets infected through the airborne route died. This is a phenomenal rate of lethality; in contrast, only about two percent of humans who contracted the illness died from it during the Spanish Flu pandemic of 1918.
So it was with concern that the scientific world noted Kawaoka’s study describing the construction of a brand-new flu virus from wild-avian-flu strain genes that coded for proteins similar to those in the 1918 pandemic virus. The resulting new pathogen was not only able to spread between ferrets—the best current animal model for human flu transmission—but it was also more severe in its effects than the original avian strain. But the story does not finish here. As an article in Nature revealed, the “controversial influenza study was run in accordance with new US biosecurity rules only after the US National Institute of Allergy and Infectious Diseases (NAID) disagreed with the university’s assessments,” thus showing the real need for reform of the current system.
Avoiding a ‘normal’ accident. While biotechnology promises tremendous public health benefits, it also holds a considerable potential for catastrophe, as these gain-of-function experiments illustrate. As scientific capabilities and work involving dangerous pathogens proliferate globally, so too do the risks and the prospects for failure—whether coming from technology or arising from human error. Indeed, in assessing the rapidly evolving life-science landscape, Jose-Luis Sagripanti of the US Army Edgewood Chemical Biological Center—the nation’s principal research and development resource for chemical and biological defenses—has argued that “current genetic engineering technology and the practices of the community that sustains it have definitively displaced the potential threat of biological warfare beyond the risks posed by naturally occurring epidemics.”
Laboratories, however well equipped, do not exist in isolation but are an integral part of a larger ecological system. As such, they are merely a buffer zone between the activities carried out inside and the greater environment beyond the laboratory door. Despite being technologically advanced and designed to ensure safety, this buffer zone is far from infallible. Indeed, as researchers from Harvard and Yale demonstrated earlier this year, there is almost a 20 percent chance of a laboratory-acquired infection occurring during gain-of-function work, even when performed under conditions of the highest and more rigorous levels of containment. Addressing the rapid expansion of gain-of-function studies is therefore both urgent and mandatory.
In December 2013, the Foundation for Vaccine Research sent a letter to the European Commission calling for a “rigorous, comprehensive risk-benefit assessment of gain-of-function research” which “could help determine whether the unique risks to human life posed by these sorts of experiments are balanced by unique public health benefits which could not be achieved by alternative, safe scientific approaches.” Given the recent developments with influenza viruses, there is a need for an independent assessment of the costs and benefits of gain-of-function research. Such independent review would allow for adopting newer and better regulations and conventions, as well as help to identify policy gaps. As David Relman of the Stanford School of Medicine recently pointed out in the Journal of Infectious Diseases, the time has come for a balanced and dispassionate discussion that “must include difficult questions, such as whether there are experiments that should not be undertaken because of disproportionately high risk.”
> true?rel=0&w=420&h=315] World War II in the Pacific
Japanese Unit 731
Biological Warfare Unit Tokyo
War Crimes Against Humanity
Japanese Imperial Army’s Unit 731 killed thousands of Chinese and Russians held prisoner in Japanese-occupied Manchuria, in experiments to develop chemical and biological weapons.
In the autumn of 1945, MacArthur acceded to granting immunity to members of Unit 731 in exchange for data of research on biological warfare. “The value to the U.S. of Japanese BW data is of such importance to national security as to far outweigh the value accruing from war crimes’ prosecution.” The BW information obtained from Japanese sources should be retained in ‘top secret’ intelligence channels and not be employed as war crimes evidence and not be fallen into the Soviet hands. The State Department disagreed over a two year period and the topic simply disappeared.
Why did the US lose interest in pursuing the issue of war criminals? China became communist, Japan was a required base for operations in Korea, and Japan became a major trading partner and economic power in the East.
1925 — Japan refuses Geneva Convention ban on biological weapons.
1932 — Japanese troops invade Manchuria. Shiro Ishii, a physician and army officer who was intrigued by germ warfare, begins preliminary experiments.
1936 — Unit 731, a biological-warfare unit disguised as a water-purification unit, is formed. Ishii builds huge compound — more than 150 buildings over six square kilometers — outside the city of Harbin, Manchuria. Some 9,000 test subjects eventually die at the compound.
1942 — Ishii begins field tests of germ warfare on Chinese soldiers and civilians. Tens of thousands die of bubonic plague, cholera, anthrax and other diseases. U.S. soldiers captured in Philippines are sent to Manchuria.
1945 — Japanese troops blow up the headquarters of Unit 731 in final days of Pacific war. Ishii orders 150 remaining ‘subjects’ killed to cover up their experimentation.
1946 — U.S. makes a deal with Ishii for germ warfare data based on human experimentation in exchange for immunity from war-crimes prosecution.
Sources: ”Factories of Death,” by Sheldon H. Harris (Rutledge, 1994)
”Prisoners of the Japanese: POWS of World War II in the Pacific,” by Gavan Daws (William Morrow, 1994), and
”UNIT 731: Japan’s Secret Biological Warefre in World War II” by Peter Williams and David Wallnce (The Free Press, 1989).
Japan’s biological weapons program was born in the 1930s, in part because Japanese officials were impressed that germ warfare had been banned by the Geneva Protocol of 1925. If it was so awful that it had to be banned under international law, the officers reasoned, it must make a great weapon. Establishment of two biological warfare Units 731 and 100 in Manchuria in 1933 because of the number of test subjects available. Harbin in Manchuria was the headquarters of Unit 731. Ishii promoted to full colonel with 3,000 Japanese working under him. In addition of bacteriological warfare, studies were also conducted on human damage done by burns, freezing, high pressure, and bullets. Former members of the unit say that at least 3,000 people and by some accounts several times that number were killed in the medical experiments in which none survived.
“After infecting him, the researchers decided to cut him open to see what the disease does to a man’s inside. I cut him open from the chest to the stomach and he screamed terribly and his face was all twisted in agony. made this unimaginable sound, he was screaming so horribly. This was all in a day’s work for the surgeons, but it really left an impression on me because it was my first time.”
The human experimentation did not take place just in Unit 731, nor was it a rogue unit acting on its own. Prince Mikasa, toured Unit 731’s headquarters in China and wrote in his memoirs that he was shown films showing how Chinese prisoners were “made to march on the plains of Manchuria for poison gas experiments on humans.” Premier Tojo personally presented an award to Ishii for his contribution to developing biological weapons.
The Japanese army regularly conducted field tests to see whether biological warfare would work outside the laboratory. Planes dropped plague-infected fleas over Ningbo in eastern China and over Changde in north-central China and plague outbreaks were later reported.
Japanese troops also dropped cholera and typhoid cultures in wells and ponds, but the results were often counterproductive. In 1942, germ warfare specialists distributed dysentery, cholera and typhoid in Zhejiang Province in China. but Japanese soldiers themselves became ill and 1,700 died of the diseases. An estimated 440,000 Chinese died of this germ warfare.
Planned Bacterial Attack on the United States.
Proposals included use of these weapons against the United States. They proposed using balloon bombs to carry disease to America and they had a plan in the summer of 1945 to use kamikaze pilots to dump plague infected fleas on San Diego.
Some Japanese generals proposed loading the balloons with weapons of biological warfare, to create epidemics of plague or anthrax in the United States. Other army units wanted to send cattle plague virus to wipe out the American livestock industry or grain smut to wipe out the crops. As it happened, 9,000 balloons each carried four incendiary and one antipersonnel bomb across the Pacific on the jet stream to create forest fires and terror from Oregon to Michigan.
As the end of the war approached in 1945, Unit 731 embarked on its wildest scheme; codenamed Cherry Blossoms at Night, the plan was to use kamikaze pilots to infest California with the plague.
Toshimi Mizobuchi, who was an instructor for new recruits in Unit 731, said the idea was to use 20 of the 500 new troops who arrived in Harbin in July 1945. A submarine was to take a few of them to the seas off Southern California, and then they were to fly in a plane carried on board the submarine and contaminate San Diego with plague-infected fleas. The target date was to be Sept. 22, 1945. As it happened, the fleet of submarine seaplane carriers that assembled was assigned to launch torpedoes at the locks in the Panama canal, but that was changed to attack the US fleet at Ulith just as the war ended.
As the Japanese army retreated from China as the war was ending, plague-infected animals were released and caused outbreaks of the plague that killed at least 30,000 people in the Harbin area from 1946 through 1948.
“Iishi and his colleagues received immunity from prosecution and … in exchange they provided a great deal of information to U.S. authorities.” In particular, they provided the results of “field tests” in which hundreds of thousands of civilians in China and eastern Russia were exposed to and died from deadly germs such as anthrax and plague.
At the outbreak of the Wusung-shanghai campaign on August 13, 1937, the Japanese army used poison gas against Chinese troops. In the succeeding eight years of war, Japan had used poison gases 1,131 times in 14 Chinese provinces.
On at least five occasions during the first two years the Japanese armed forces tried to employ bacteriological warfare in China. They have tried to produce epidemics of plague in Free China by scattering plague-infected materials with airplanes.
These five times are: October 4, 1940, when Japanese airplane dropped plague bacteria at Chuhsien in Chechiang province which caused the deaths of 21 people. On the 29th of the same month, Japanese airplane spread plague bacteria at Ningpo, Chechiang which caused the deaths of 99 people. On November 28 of the same year, Japanese airplanes dropped a large quantity of germs at Chinhua but no deaths were reported. In January 1941 Japan spread plague germs in Suiyuan and Ninghsia provinces and again in Shansi that caused serious epidemic outbreaks of plague in these areas. When too many Japanese soldiers also died, the attacks were suspended.
Japan Admits Dissecting WW-II POWs
On May 5, 1945, an American B-29 bomber was knocked down over southern Japan. Eight American airmen prisoners were made available for medical experiments at Kyushu Imperial University. The eight were dissected organ by organ while they were still alive.
This is the only site where Americans were incontrovertibly used in dissections and the only known site where experiments were done in Japan. Kyushu University, Fukuoka, is midway between Hiroshima and Nagasaki.
Thirty people were brought to trial by an Allied War Crimes Tribunal in Yokohama, Japan, on March 11, 1948. Charges included vivisection and wrongful removal of body parts; 23 were found guilty of various charges. Five of the guilty were sentenced to death. None of the death sentences was carried out. By 1958, all those convicted were free. The Soviet Union also held trials. Sentences there were carried out.
War Crimes Trial
High-level Japanese war criminals were tried by the International Military Tribunal for the Far East. The prosecution team was made up of justices from eleven Allied nations: Australia, Canada, China, France, Great Britain, India, the Netherlands, New Zealand, the Philippines, the Soviet Union and the United States of America. The Tokyo trial lasted two and a half years, from May 1946 to November 1948. The principle charges were making aggressive war and allowing atrocities against POWs and civilians.
Two of the twenty-eight defendants died of natural causes during the trial. One had a mental breakdown on the first day of trial, was sent to a psychiatric ward and was released in 1948. The remaining twenty-five were found guilty. Seven were sentenced to death by hanging, sixteen to life imprisonment, and two to lesser terms. All seven sentenced to death were found to be guilty of inciting mass-scale atrocities, among other counts, and hanged Dec. 23. Three of the sixteen sentenced to life imprisonment died in prison. The remaining thirteen were paroled between 1954 and 1956, with less than eight years in prison for their crimes against millions of people.
ACCUSED 0 2 2 3 3 3 3 3 5 5 SENTENCE NOTES
1 7 9 1 2 3 5 6 4 5
ARAKI G G X X X X X X X X Life Imp. Paroled 1955
DOIHARA G G G G G X G G G O Death
HASHIMOTO G G X X X X X – – – Life Imp. Paroled 1954
HATA G G G G G X X X – G Life Imp. Paroled 1955
HIRANUMA G G G G G X X G X X Life Imp. Paroled 1955
HIROTA G G X X X X X X – G Death
HOSHINO G G G G G X X X X – Life Imp. Paroled 1955
ITAGAKI G G G G G X G G G – Death
KAYA G G G G G X ? ? ? O Life Imp. Paroled 1955
KIDO G G G G G X X X X X Life Imp. Paroled 1955
KIMURA G G G G G – – – G G Death
KOISO G G G G G X X – – G Life Imp. Died 1950
MATSUI X X X X X X X X – G Death **
MINAMI G G X X X X X – – – Life Imp. Paroled 1954
MUTO G G G G G X X – G G Death
OKA G G G G G X X – – – Life Imp. Paroled 1954
OSHIMA G X X X X X X – – – Life Imp. Paroled 1955
SATO G G G G G X X – – – Life Imp. Paroled 1956
SHIMADA G G G G G X X – – – Life Imp. Paroled 1955
SHIRATORI G X X X X – – – – – Life Imp. Died 1949
SHIGEMITSUX G G G G G X X – G 7 years Paroled 1950 Foreign Minister 1954
SUZUKI G G G G G X X X X – Life Imp. Paroled 1955
TOGO G G G G G X X X – – 20 years Died 1948
TOJO G G G G G G X – G O Death **
UMEZU G G G G G – – X X X Life Imp. Died 1949
Blank: No indictment; G: Guilty; X: Not Guilty; O: Other.** – Enshrined as “martyr” at the Yasukuni Shrine,
national war memorial dedicated to the
Shinto code of bushido – the way of the soldier.
Researcher Yoshihiro Kawaoka of the University of Wisconsin-Madison published an article in the journal Cell Host and Microbe in June revealing that he had taken genes from the deadly human 1918 Spanish Flu and inserted them into the H5N1 avian flu to make a new virus—one which was both far deadlier and far more capable of spreading than the original avian strain http://thebulletin.org/making-viruses-lab-deadlier-and-more-able-spread-accident-waiting-happen7374